There is evidence that endotheliopathy is intrinsic to obesity/insulin resistance and, in turn, type 2 diabetes. Alterations in vasomotor function, specifically an imbalance between vasodilation and vasoconstriction, occurring in the obese/insulin resistant prediabetic stage is thought to contribute to the accelerated rates of atherosclerotic vascular disease in type 2 diabetes. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. In addition to its effects on vascular tone, ET-1 has been linked to the initiation and development of atherosclerosis. Importantly, oxidative stress is associated with obesity/insulin resistance, impaired endothelium-dependent vasodilation and increased ET-1 production and activity. The specific aims of the present proposal will be to determine: 1) whether the vasoconstrictor activity of endogenous ET-1 is increased in obese/insulin resistant adult humans; 2) if oral vitamin C supplementation reduces endogenous ET-1 vasoconstrictor activity in obese/insulin resistant adults as much or more than regular aerobic exercise; and 3) if oral vitamin C supplementation improves endotheliumdependent vasodilation in obese/insulin resistant adult humans as much or more than regular aerobic exercise; and to determine whether improvements in endothelial vasodilation is due, at least in part, to reduced ET-1 vasoconstrictor activity. To address these aims, 252 middle-aged and older obese/insulin resistant and lean/insulin sensitive adult humans will be studied. Endogenous ET-1 vasoconstrictor activity will be assessed by changes in forearm blood flow (plethysmography) in response to intra-arterial infusion of selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1. In addition, the vasodilator response to both acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. Endogenous ET-1 vasoconstrictor activity will also be assessed before and after a 12-week intervention of either oral vitamin C supplementation (500 mg/d) or aerobic exercise training in obese/insulin resistant adults. The results of the proposed study should provide clinically important information regarding the activity of the ET-1 system with obesity/insulin resistance; and the efficacy of vitamin C supplementation in reducing ET-l-mediated vasoconstriction and, in turn, improving endothelial vasomotor regulation in obese/insulin resistant adults.

R01HL076434

2004-06-01

2010-05-31